Showing papers by "Robert M. Grant published in 2004"

Decline in HIV infectivity following the introduction of highly active antiretroviral therapy.

Abstract: Objective: Little is known about the degree to which widespread use of antiretroviral therapy in a community reduces uninfected individuals’ risk of acquiring HIV. We estimated the degree to which the probability of HIV infection from an infected partner (the infectivity) declined following the introduction of highly active antiretroviral therapy (HAART) in San Francisco. Design: Homosexual men from the San Francisco Young Men’s Health Study, who were initially uninfected with HIV, were asked about sexual practices, and tested for HIV antibodies at each of four follow-up visits during a 6-year period spanning the advent of widespread use of HAART (1994 to 1999). Methods: We estimated the infectivity of HIV (per-partnership probability of transmission from an infected partner) using a probabilistic risk model based on observed incident infections and self-reported sexual risk behavior, and tested the hypothesis that infectivity was the same before and after HAART was introduced. Results: A total of 534 homosexual men were evaluated. Decreasing trends in HIV seroincidence were observed despite increases in reported number of unprotected receptive anal intercourse partners. Conservatively assuming a constant prevalence of HIV infection between 1994 and 1999, HIV infectivity decreased from 0.120 prior to widespread use of HAART, to 0.048 after the widespread use of HAART – a decline of 60% (P ¼ 0.028). Conclusions: Use of HAART by infected persons in a community appears to reduce their infectiousness and therefore may provide an important HIV prevention tool.

Persistence of primary drug resistance among recently HIV-1 infected adults.

Abstract: Objectives: Primary, or transmitted, drug resistance is common among treatment naive patients recently infected with HIV-1, and impairs response to anti-retroviral therapy. We previously observed that patients with secondary resistance (developed in response to anti-retroviral treatment) who chose to stop an anti-retroviral regimen experience rapid overgrowth of drug resistant viruses by wild-type virus of higher pol replication capacity. We sought to determine if primary drug resistance would be lost at a rapid rate, and viral pol replication capacity would increase, in the absence of treatment. Methods: We tracked drug resistance phenotype, genotype, viral pol replication capacity (single cycle recombinant assay incorporating a segment of the patient pol gene [pal RCl), plasma HIV-1 RNA, and CD4 T cell counts in the absence of treatment among patients in early HIV-1 infection. Results: Six of 22 patients had evidence of primary drug resistance to at least one class of drug; three resistant to protease inhibitors, three resistant to non-nucleoside reverse transcriptase inhibitors, and four resistant to nucleoside reverse transcriptase inhibitors. All six patients maintained evidence of drug resistance for the period of observation. Among patients with baseline primary drug resistance pol RC did not increase over time. Conclusion: The selection environment of early infection is determined by immune pressure, and stochastic events, not viral pol replication capacity. In contrast to secondary resistant infections that are rapidly overgrown when therapy is stopped, primary drug resistance persists over time. Surveillance and clinical detection of primary resistance is feasible in the first year of infection.

Higher CD4+ T Cell Counts Associated with Low Viral pol Replication Capacity among Treatment-Naive Adults in Early HIV-1 Infection

Abstract: BACKGROUND Infection with primary drug-resistant human immunodeficiency virus type 1 (HIV-1) has been associated with higher CD4(+) T cell counts in drug-naive patients, suggesting that altered viral pol replication capacity (RC) associated with drug resistance diminishes immune injury in vivo, independent of exposure to drugs. METHODS Virus replication over a single cycle was measured by use of a viral test vector containing patient-derived HIV-1 protease and reverse transcriptase gene segments. RESULTS Among 191 recently infected patients, pol RC ranged widely, with only 6% of the variance explained by drug-resistance mutations. Patients infected with a virus with a low pol RC (

Human immunodeficiency virus type 1 superinfection was not detected following 215 years of injection drug user exposure.

Abstract: Evidence for human immunodeficiency virus type 1 (HIV-1) superinfection was sought among 37 HIV-1-positive street-recruited active injection drug users (IDUs) from the San Francisco Bay area. HIV-1 sequences from pairs of samples collected 1 to 12 years apart, spanning a total of 215 years of exposure, were generated at p17 gag, the V3-V5 region of env, and/or the first exon of tat and phylogenetically analyzed. No evidence of HIV-1 superinfection was detected in which a highly divergent HIV-1 variant emerged at a frequency >20% of the serum viral quasispecies. Based on the reported risk behavior of the IDUs and the HIV-1 incidence in uninfected subjects in the same cohort, a total of 3.4 new infections would have been expected if existing infection conferred no protection from superinfection. Adjusted for risk behaviors, the estimated relative risk of superinfection compared with initial infection was therefore 0.0 (95% confidence interval, 0.00, 0.79; P = 0.02), indicating that existing infection conferred a statistically significant level of protection against superinfection with an HIV-1 strain of the same subtype, which was between 21 and 100%.

Overview: brain tumour diagnosis and management/royal college of physicians guidelines

Abstract: This article is intended to reflect the current level of services for patients with brain tumours in the UK, “warts and all” I have taken the evidence from first hand experiences auditing practice and implementation of the Royal College of Physicians guidelines for good practice in three of the four neuroscience centres in Scotland I anticipate the findings are no better or no worse than what you will find in your local neuroscience centre I hope it encourages you to work closely with neuropathology, neuro-radiology, neurosurgical and clinical oncological colleagues to improve the standard of care for patients with brain tumours Hopefully this review will provide some evidence and support for submissions to improve the service in your local centre Primary brain tumours, although numerically fairly uncommon (incidence 8/100 000 per year), have a major impact on family and working life as they are the most common solid tumour in children and the eighth most common cancer in people of working age1 Cerebral gliomas account for > 90% of primary brain tumours and are the fifth most common cause of death from cancer under the age of 65 years They have a five year survival of only 18% Patients with brain tumours are rare in general practice (four or five new cases in one general practitioner’s (GP’s) working lifetime), yet they remain a common concern of patients and GPs Primary and secondary brain tumours present with similar symptoms and can be difficult to distinguish either clinically or by imaging Usually, patients are referred to a physician or neurologist at their local major hospital Brain imaging demonstrates an abnormality that could be a tumour The patient may then be referred to a neurosurgeon Care pathways can be depicted as a “timeline” (fig 1) At each decision time point patients are …

Randomized, controlled trial of therapy interruption in chronic HIV-1 infection.

Abstract: Background Approaches to limiting exposure to antiretroviral therapy (ART) drugs are an active area of HIV therapy research. Here we present longitudinal follow-up of a randomized, open-label, single-center study of the immune, viral, and safety outcomes of structured therapy interruptions (TIs) in patients with chronically suppressed HIV-1 infection as compared to equal follow-up of patients on continuous therapy and including a final therapy interruption in both arms. Methods and Findings Forty-two chronically HIV-infected patients on suppressive ART with CD4 counts higher than 400 were randomized 1:1 to either (1) three successive fixed TIs of 2, 4, and 6 wk, with intervening resumption of therapy with resuppression for 4 wk before subsequent interruption, or (2) 40 wk of continuous therapy, with a final open-ended TI in both treatment groups. Main outcome was analysis of the time to viral rebound (>5,000 copies/ml) during the open-ended TI. Secondary outcomes included study-defined safety criteria, viral resistance, therapy failure, and retention of immune reconstitution. There was no difference between the groups in time to viral rebound during the open-ended TI (continuous therapy/single TI, median [interquartile range] = 4 [1–8] wk, n = 21; repeated TI, median [interquartile range] = 5 [4–8] wk, n = 21; p = 0.36). No differences in study-related adverse events, viral set point at 12 or 20 wk of open-ended interruption, viral resistance or therapy failure, retention of CD4 T cell numbers on ART, or retention of lymphoproliferative recall antigen responses were noted between groups. Importantly, resistance detected shortly after initial viremia following the open-ended TI did not result in a lack of resuppression to less than 50 copies/ml after reinitiation of the same drug regimen. Conclusion Cycles of 2- to 6-wk time-fixed TIs in patients with suppressed HIV infection failed to confer a clinically significant benefit with regard to viral suppression off ART. Also, secondary analysis showed no difference between the two strategies in terms of safety, retention of immune reconstitution, and clinical therapy failure. Based on these findings, we suggest that further clinical research on the long-term consequences of TI strategies to decrease drug exposure is warranted.

Relating HIV-1 Sequence Variation to Replication Capacity via Trees and Forests - eScholarship

Abstract: The problem of relating genotype (as represented by amino acid sequence) to phenotypes is distinguished from standard regression problems by the nature of sequence data. Here we investigate an instance of such a problem where the phenotype of interest is HIV-1 replication capacity and contiguous segments of protease and reverse transcriptase sequence constitutes genotype. A variety of data analytic methods have been proposed in this context. Shortcomings of select techniques are contrasted with the advantages afforded by tree-structured methods. However, tree-structured methods, in turn, have been criticized on grounds of only enjoying modest predictive performance. A number of ensemble approaches (bagging, boosting, random forests) have recently emerged, devised to overcome this deficiency. We evaluate random forests as applied in this setting, and detail why prediction gains obtained in other situations are not realized. Other approaches including logic regression, support vector machines and neural networks are also applied. We interpret results in terms of HIV-1 reverse transcriptase structure and function.

Relating HIV-1 sequence variation to replication capacity via trees and forests.

Abstract: The problem of relating genotype (as represented by amino acid sequence) to phenotypes is distinguished from standard regression problems by the nature of sequence data. Here we investigate an instance of such a problem where the phenotype of interest is HIV-1 replication capacity and contiguous segments of protease and reverse transcriptase sequence constitutes genotype. A variety of data analytic methods have been proposed in this context. Shortcomings of select techniques are contrasted with the advantages afforded by tree-structured methods. However, tree-structured methods, in turn, have been criticized on grounds of only enjoying modest predictive performance. A number of ensemble approaches (bagging, boosting, random forests) have recently emerged, devised to overcome this deficiency. We evaluate random forests as applied in this setting, and detail why prediction gains obtained in other situations are not realized. Other approaches including logic regression, support vector machines and neural networks are also applied. We interpret results in terms of HIV-1 reverse transcriptase structure and function.

HIV-1 superinfection and viral diversity.

Abstract: Objective: Sequential acquisition of viral variants, or HIV-1 superinfection, has been proposed to explain the high fractions of recombinant viruses observed in some geographical regions, but only a few cases of superinfection in humans have been reported. Animal models suggest that susceptibility to superinfection may be restricted to a short period of time after initial infection, possibly due to maturation of broad antiviral immune responses. Methods: A mathematical model involving a system of differential equations was developed to identify transmission and superinfection patterns that would lead to the observed global patterns of viral diversity. Results: Requirements for a high prevalence of infections involving recombinant viruses include high viral infectivity, the presence of highly sexually active core groups, and introduction of divergent viruses early in the epidemic spread of HIV-1. Restricted superinfection could explain the persistent predominance of single virus subtypes in regions with well-established HIV-1 epidemics. The rate of recombination within individuals was not strongly related to recombinant fractions in populations. Conclusions: HIV-1 superinfection restricted to early HIV-1 infection could account for the high fraction of recombinant virus infections observed in populations. The relationship between recombination in cellular infections and recombinant fractions in populations is complex and depends on epidemiological factors and biological factors that can be modeled.

HIV-producing T cells in cerebrospinal fluid.

Abstract: Summary In HIV-1–infected subjects, the magnitude of HIV-1 viral load in cerebrospinal fluid (CSF) correlates with the CSF white cell count. To determine whether HIV-1–producing T cells appear in CSF and whether their percentage and number correlate with viral load in CSF, we developed a flow cytometric assay that detects HIV-1–producing T cells by identifying intracellular p24 HIV-1 antigen. We found that most CSF T cells were not HIV-1 producing, even when cell-free viral load in CSF was high. Most activated T cells in CSF were also not HIV-1 producing, but the activated CD38+ CD4 T-cell fraction in CSF was independently associated with the fraction of HIV-1–producing T cells in CSF. We conclude that HIV-1–producing T cells appear in CSF and that their percentage and number correlate with cell-free viral load in CSF, even though the CSF total white cell count remains the best predictor for CSF viral load. In HIV-1 infection, CSF white cell counts seem to contain a large number of uninfected cells. White cell counts and viral load in CSF may result from systemic inflammation and immune activation.

Virological evaluation of the 'Ottawa case' indicates no evidence for HIV-1 superinfection.

Abstract: An HIV-1 infected man who experienced rapid disease progression and poor response to therapy after starting a new sexual relationship with an infected partner is known as the 'Ottawa superinfection case'. Subsequent analysis of viral sequences of protease, reverse transcriptase, Gag p17, and Env V3 provided no evidence for the acquisition of genetically divergent viruses before disease progression or drug resistance during virological failure of combination therapy. Whether HIV-1 superinfection contributes to disease progression or the spread of drug-resistant HIV-1 remains unknown.

The Clinical Implications of Reduced Viral Fitness.

Abstract: Viral fitness, defined as the extent of viral adaptation to the host environment, arises from tissue tropism, immune system evasion, drug resistance, and viral replication capacity. The fitness of wild-type and drug-resistant HIV-1 varies widely, associating with plasma viremia, CD4+ T-cell count, and clinical progression. HIV-1 fitness may be measured in competitive culture assays, single cycle assays, or single cycle assays based on a subgenomic fragment of HIV-1, which has been standardized as the replication capacity assay (pol RC). During virologic failure of antiretroviral therapy, CD4 T-cell counts remain elevated while pol RC declines and remains durably lower because of drug-selected changes in the gag and pol genes. CD4 T-cell sparing also is observed among patients without evidence of drug resistance who carry a low pol RC virus. Reduced HIV-1 replication capacity and virulence may occur because of drug resistance or viral escape from host immune responses.

Response to Foulkes and De Gruttola

Abstract: This note is the authors' response to the Reader's Reaction provided by Foulkes and De Gruttola as published in Statistical Applications in Genetics and Molecular Biology